Pharmaceutical dosage form bearing pregnancy-friendly indicia

ABSTRACT

A pharmaceutical dosage form comprising at least one active ingredient and destined for administration to pregnant women. The pharmaceutical dosage form bears pregnancy-friendly indicia apt to improve patient compliance with medically recommended dosage regimen resulting in improved product effectiveness. The pregnancy-friendly indicia is also apt to diminish the incidence of erroneous dispensing of or erroneous ingestion of pharmaceutical dosage forms not intended for pregnant women. Also disclosed is a method for achieving improved patient compliance resulting in improved product effectiveness. Also disclosed is a method for diminishing the incidence of erroneous dispensing of or erroneous ingestion of dosage forms not intended for pregnant women. Said methods comprising providing a pharmaceutical dosage form, intended for use by pregnant women, bearing pregnancy-friendly indicia apt to graphically distinguish dosage forms intended to be used during pregnancy from others.

FIELD OF THE INVENTION

[0001] The present invention relates to pharmaceutical dosage formsintended for use during pregnancy.

BACKGROUND OF THE INVENTION

[0002] During pregnancy a variety of medical conditions requiretreatment with therapeutic agents. For instance, in Canada, excessivenausea and vomiting, possibly leading to hyperemesis gravidarum, areroutinely treated with the prescription drug Diclectin® which contains amixture in equal amounts of two active ingredients, namely pyridoxineHCl and doxylamine succinate.

[0003] Other conditions, pre-existing or developed during pregnancy, forexample: diabetes, hypertension, blood cloths, depressive illness andheart disease are also commonly treated with prescription drugs.

[0004] In the case of pre-existing medical conditions numerous studieshave shown that women have a tendency to abruptly stop taking theirmedications upon learning of the pregnancy, due to the perceived fear ofbirth defects¹. In many cases, the risk to the health of the expectantmother and her baby is much higher if she stops or reduces her treatmentthan if she keeps taking the required medications.

[0005] Because of this perceived risk of harm to the fetus, otherwiseknown as the teratogenic risk, it is common for expectant mothers todiscontinue taking a prescribed drug or to voluntarily diminish theprescribed dosage regimen. This often leads to dosage levels belowtherapeutic ranges in turn leading patients and the medical community toincorrectly conclude that a particular drug is clinically ineffective.

[0006] Discontinuing or altering drug therapy, often against competentmedical prescription, may have grave consequences indeed. The health ofthe expectant mother and vicariously of the fetus may be put at greatrisk because of poor compliance with competent medical prescription. Inmany instances, the teratogenic risks must be weighed against the riskof catastrophic illness or worsening condition on the part of theexpectant mother.

[0007] Even discounting the particular problem of patient complianceduring pregnancy, drug therapy patient compliance is a widespread anddifficult problem in the medical community. Non-compliance withprescribed drug dosage regimen is a huge health problem for patients ingeneral. For example, it is estimated that less than 25% of outpatientswill complete a 10 day course of antibiotic therapy for a strep throator otitis media.

[0008] Matsui² described that non-compliance with prescribed medicationregimens may take many forms, including failure to fill theprescription, incorrect dosage, improper dosing interval, and prematurediscontinuation of the drug. Of course, the problem of non-compliance ismagnified during pregnancy due to the importance of fetal safety.³

[0009] Whenever women delay or discontinue use of medications duringpregnancy due to fears related to fetal safety, the result may be aworsening of the condition and hospitalisation with use of multiple drugtherapy. Furthermore, depending of the underlying condition, theworsening of the condition has serious consequences even includingsuicidal ideation. Einarson showed in her study¹ on abruptdiscontinuation of psychotropic drugs during pregnancy due toteratogenic fears, that 70.3% of women reported physical andpsychological adverse effects to the point that 29.7% reported suicidalideation (one third of them were hospitalised).

[0010] Despite these appalling statistics, the perception of theexpectant mother remains shrouded by well-known errors of the past suchas the widely publicized cases of thalidomide-induced fetalmalformations. The graphic evidence of birth defects attributed toThalidomide exposure during early pregnancy has left a teratogenicitystigma on all medications. Hence, it is commonly thought that allmedications are to be avoided during pregnancy. In the study entitled“Prevention of Unnecessary Pregnancy Terminations by Counselling Womenof Drug, Chemical, and Radiation Exposure During the First Trimester”,(1990)⁴, Koren showed that pregnant women exposed to drugs that areknown to be non teratogenic, still perceive that their born-to-be babyhas a 24% chance to suffer a major birth defect. This is about the samerisk as an intra-uterine exposure to Thalidomide.

[0011] Scientific studies aimed at measuring the risk of drugs duringpregnancy and patient education and counseling have so far been at theforefront of efforts to achieve better patient compliance with medicalprescription.

[0012] However, even in the case of drugs having an extensivelydemonstrated record of fetal innocuousness, such as Diclectin® used tocurb nausea and vomiting, the perception of latent risk remains. Thisperception of risk is of course carried over from the negativeexperiences of thalidomide which was also prescribed for nausea andvomiting during pregnancy and which was also provided as an oral dosageform. However, in reality, the active ingredient thalidomide and theactive ingredients of Diclectin®, namely pyridoxine HCl and doxylaminesuccinate are completely unrelated. The risk perception carried-overfrom thalidomide is made apparent from patient compliance inquiries.Patient compliance with a medically prescribed dosage regimen ofDiclectin® is clearly below what is recommend in the medical profession.

[0013] Even physicians and pharmacists are anxious about their liabilityassociated with prescription or dispensing of medications to pregnantwomen. In the study by Pole⁵, it was shown that even health careprofessionals, after reading four different labels (all of them statingthat drug is safe to be used in pregnancy), have evaluated these labels,as bearing a residual risk. They were unable to fully perceive or acceptthat medication is safe to be used in pregnancy. Patients, physiciansand pharmacists are also worried about erroneous ingestion or dispensingof drugs not intended for use during pregnancy.

[0014] Despite the enormous volume of scientific evidence supportingDiclectin® harmlessness to the fetus, pregnant women persistently do notfollow their physician's recommendation as to the adherence toDiclectin® dosage regimen. In most cases, women voluntarily reduce thedosage by half. In fact, they do not comply with the proper dosageregimen for Diclectin® to the point that some woman and some physiciansbelieve that the medication is not effective. Therefore, non-complianceoften results in a perception of product effectiveness failure.

[0015] Due to non-compliance with medical prescription, patients usingless than prescribed amounts of Diclectin® will often find themselves insub-therapeutic state. This prevents the medication from being effectiveand may aggravate the mother's condition to the point of developinghyperemesis gravidarum (HG). HG is the most severe end of nausea andvomiting during pregnancy, when a pregnant woman suffers from loss ofmore than 5% of her pre-pregnancy body weight, dehydration, acid-basedisturbances, ketonuria and electrolyte imbalance. At this stage,physicians use intravenous medications that are often not recognised forsafe use during pregnancy in order to control maternal condition. Theuse of these medications poses an unnecessary risk to the fetus. If thislast resort medication appears to be ineffective due to thedeterioration of the woman's condition, a therapeutic abortion may evenbe considered⁶.

[0016] In order to diminish potential for birth defects a vitamin intakeis now medically recommended during pregnancy. For example, clinicalevidence shows that taking folic acid before conception and during thefirst trimester of pregnancy may prevent up to 72% of the congenitalabnormalities spina bifida and anencephaly⁷. Despite this, pregnantwomen are generally non compliant with recommended folic acid intaketreatment thus putting an unborn child at an increased risk of majorbirth defect.

[0017] The situation is even worse if pregnant woman has been on a drugtherapy that interferes with folic acid receptors (e.g., phenobarbital,phenytoin, carbamazepine, valproic acid). In this case, a pregnant womanis even at greater risk for having a baby with birth defect if she isnot compliant.

[0018] Thus there remains an important need for innovative solutions toachieve better patient compliance of vitamins or drugs recommended foruse during pregnancy.

OBJECTS OF THE INVENTION

[0019] An object of the present invention is therefore to provide animproved oral dosage form for, inter alia, achieving better patientcompliance with vitamins or drugs intended for use during pregnancy.

[0020] Another object is to provide a method for improving patientcompliance of pregnant women by diminishing their perception ofteratogenic risk and by direct implication to improve producteffectiveness of dosage forms containing at least one active ingredientand intended for use by pregnant women.

[0021] A further object is to provide a method for diminishing theincidence of erroneous ingestion by pregnant women or of erroneousdispensing by pharmacists of therapeutic agents not prescribed to saidpregnant women.

SUMMARY OF THE INVENTION

[0022] More specifically, in accordance with the present invention,there is provided a pharmaceutical dosage form comprising at least oneactive ingredient, such as for example a vitamin supplement or asynergistic combination of pyridoxine HCl and doxylamine succinate, anddestined for administration to pregnant women, the pharmaceutical dosageform bearing pregnancy-friendly indicia. In a preferred embodiment thepregnancy-friendly indicia is in the shape of a graphical illustrationof a pregnant woman applied to the dosage form itself or to itspackaging. In a most preferred embodiment, the dosage form is destinedfor oral administration.

[0023] Also provided is a method of diminishing the perception ofteratogenic risk among pregnant women taking a pharmaceutical dosageform containing at least one active ingredient. The method comprisingproviding said pharmaceutical dosage form bearing pregnancy-friendlyindicia, preferably in the shape of a graphical illustration of apregnant woman applied to the dosage form itself or to its packaging.

[0024] Also provided is a method of improving patient compliance ofpregnant women with medically recommended dosage regimen of at least oneactive ingredient. The method comprising providing a pharmaceuticaldosage form bearing pregnancy-friendly indicia. Improving patientcompliance also leads to improved product effectiveness because producteffectiveness is linked to patient compliance. Thus, the method of thepresent invention also leads to improved product effectiveness.

[0025] Also provided is method of diminishing the incidence of erroneousingestion by pregnant women or of erroneous dispensing by pharmacists oftherapeutic agents not prescribed to said pregnant women. The methodcomprising providing a pharmaceutical dosage form comprising at leastone active ingredient prescribed to said pregnant women, the dosage formbearing pregnancy-friendly indicia apt to graphically distinguish dosageforms intended to be used during pregnancy from others.

[0026] Other objects, advantages and features of the present inventionwill become more apparent upon reading of the following non-restrictivedescription of preferred embodiments thereof, given by way of exampleonly with reference to the accompanying drawing.

BRIEF DESCRIPTION OF THE DRAWINGS

[0027]FIG. 1 is a pictorial representation of an improved oral dosageform in accordance with the present invention and bearing a visibleindicia apt to achieve improved patient compliance.

DESCRIPTION OF THE PREFERRED EMBODIMENT

[0028] The main object of the present invention is therefore to providean improved oral dosage form for achieving better patient compliancewith drugs prescribed for use during pregnancy. This objective issurprisingly and effectively achieved by applying pregnancy-friendlyindicia on the dosage form. Dosage form is understood to encompass itspackaging. By “pregnancy-friendly” indicia is meant any graphical ortextual representation apt to be easily recognized as indicative of asafe medication for taking during pregnancy.

[0029] In a most preferred embodiment, the pregnancy-friendly indiciaare a graphical representation of the profile of a pregnant woman havinga hand resting on her stomach region. Such graphical representation isillustrated in FIG. 1 and has a particularly comforting effect onexpectant mothers and have been statistically shown to substantiallylower the perception of teratogenic risk and consequently lead toelevated patient compliance. Such evidence is presented in the examplesprovided below.

EXAMPLE 1

[0030] A study was conducted with 12 pregnant women. This study wasaimed at testing if pregnancy-friendly indicia such as the indiciaillustrated in FIG. 1 may have a positive impact by reducing theperception of teratogenic risk of a drug taken during pregnancy, and ifit is the case, which kind of design is most effective in improvingpatient compliance.

[0031] Different designs of pregnancy-friendly indicia were printed ontablets. This aim was to ascertain if, when used, those indicia wouldincrease the patients' confidence in taking the tablet during pregnancyby reducing the perception of teratogenic risk. Diminishing theperception of teratogenic risk would consequently improve patientcompliance and as a result achieve better treatment effectiveness.

[0032] The study revealed while all pregnancy-friendly indicia arehelpful at diminishing the perception of teratogenic risk, the mostpreferred graphical representation is that of FIG. 1. The graphicalrepresentation shown in FIG. 1 would indicate in a clear and precisefashion that the medication has been specifically designed for thepregnant woman.

[0033] This surprising positive effect on patient compliance would ofcourse translate itself in the effectiveness of a vitamin or drugtreatment and a concurrent reduction of medical complications for thepregnant woman and the fetus.

EXAMPLE 2

[0034] To further validate the findings disclosed in Example 1, anobservational, prospective survey on pregnant women in family practiceoffices and obstetrician offices was conducted. The statistical toolused for measuring the objective of the study (how reassured about fetalsafety woman feels taking one or the other tablet once prescribed tothem) was a validated scientific tool for subjective measurements: avisual analog scale (VAS) from 1-5 (1 being the least safe and 5 beingthe most safe). Patients were told that the prescribed drug, in tabletform, was safe for use in pregnancy and were asked to label on the VAShow reassured about fetal safety they felt when taking the tablet. Theywere shown two different tablets, one plain white and the other whitewith the illustration of FIG. 1 applied to the tablet.

[0035] Data was collected from 132 pregnant women and the results areshown in the table below: Test: Dual-Sample Assuming Equal VariancesTablet with preg- nancy-friendly indi- Plain White tablet cia as perFIG. 1 Observations 132 132 Mean Risk 2,5227 3,6969 Perception Variance1,2132 1,3120 P (T <= t) one- P < 0.0001 tail

[0036] The study clearly showed superiority of the tablet with a printedpregnant woman concerning the perception of the teratogenic risk(results were statistically significant with P<0.0001). The P value of0.0001 signifies that the result of this study as 1/10,000 chance to bethe result of chance only. If we repeat this study 10,000 times, in9,999 cases, the same results would be obtained. Usually P<0.05 isrecognized as medically significant.

[0037] Thus, in the sample group of 132 pregnant women, 23.4% felt morereassured about the fetal safety of taking the tablet with a printedpregnant woman as shown in FIG. 1, than a plain white tablet.

[0038] Of course, these results would translate themselves directly intoimproved patient compliance by a margin of at least 23.4%. Thus, astrong conclusion emerges that the presence of pregnancy-friendlyindicia on a vitamin or drug to be taken during pregnancy willsignificantly reduce teratogenic risk perception and by the same tokenimprove patient compliance with prescribed dosage regimen.

[0039] Although the present invention has been described hereinabove byway of preferred embodiments thereof, it can be modified, withoutdeparting from the spirit and nature of the subject invention as definedin the appended claims. More specifically, the exact appearance ofpregnancy-friendly indicia is variable with the understanding that someindicia will induce greater patient compliance than others. Also, it isto be understood that although examples were given in relation to oraltablets, other pharmaceutical dosages forms are of course covered by thepresent invention. Thus, pregnancy-friendly indicia may appear on theactual dosage form, such as tablet, sugar coated tablet, sublingualtablet, caplet, capsule, gel capsule, chewable tab, pill, suppository,powder, vial, ampoule, pre-filled syringe, nasal spray, pastille, syrup,drops, vaginal ovule, subcutaneous implant, transdermal gel, transdermalpatch, transmucausal strip, pouch, or may also appear on the packagingand labeling of the dosage form.

REFERENCES

[0040] 1. Einarson A., Selby P., Koren G., Abrupt discontinuation ofpsychotropic drugs during pregnancy: fear of teratogenic risk and impactof counseling, J. psychiatry Neurosci 2001; 26(1): 44-48

[0041] 2. Matsui D., Drug compliance in pediatrics: Clinical andresearch issues. Ped Clin N Amer 1997;44(1):1-14

[0042] 3 Anke M., et al., Questions about drugs: how do pregnant womensolve them? Pharm world Sci 1994 Dec. 2;16(6):254-9; and

[0043] Olesen C., Sondergaard C., Do Pregnant Women Report Use ofDispensed Medications?, Epidemiology 2001; 12(5):497-501

[0044] 4. Koren G., Pastuszak A., Prevention of Unnecessary PregnancyTerminations by Counselling Women on Drug, Chemical, and RadiationExposure During the First Trimester, Teratology 1990;41(6):657-61

[0045] 5. Pole M., Einarson A., Pairaudeau N.& al., Drug Labeling andRisk Perceptions of Teratogenicity: A Survey of Pregnant Canadian Womenand Their Health Professionals, J Clin. Pharmacol. 2000;40: 573-577

[0046] 6. Mazzotta P., Stewart D., Koren G., Magee L A. Factorsassociated with elective termination of pregnancy among Canadian andAmerican women with nausea and vomiting of pregnancy. J. PsychosomObstet. Gynecol. 2001;22(1):7-12

[0047] 7 Czeizel A E, Dudas I: Prevention of the first occurance ofneural tube defects by periconceptional vitamin supplementation. N Eng JMed 1992; 327:1832-1835; and

[0048] Pastuszak A., Bhatia D., Okotore B., Koren G., The Effectivenessof Preconceptional Counseling on Women's Compliance with Folic AcidSupplementation, Maternal-Fetal Toxicology, A Clinician's Guide,Third-Edition, 2001:141-149

What is claimed is:
 1. A pharmaceutical dosage form comprising at leastone active ingredient and destined for administration to pregnant women,said pharmaceutical dosage form bearing pregnancy-friendly indiciaadapted to graphically confirm the non-teratogenic aspect of thepharmaceutical dosage form.
 2. The pharmaceutical dosage form of claim 1wherein the dosage form is an oral dosage form.
 3. The pharmaceuticaldosage form of claim 2 wherein the dosage form is a tablet.
 4. Thepharmaceutical dosage form of claim 1 wherein the at least one activeingredient comprises at least one vitamin.
 5. The pharmaceutical dosageform of claim 1 wherein the at least one active ingredient comprises theactive ingredients pyridoxine HCl and doxylamine succinate.
 6. Apharmaceutical dosage form comprising at least one active ingredient anddestined for administration to pregnant women, said pharmaceuticaldosage form bearing pregnancy-friendly indicia adapted to graphicallyconfirm the non-teratogenic aspect of the pharmaceutical dosage form,said indicia being in the shape of a graphical illustration of apregnant woman applied to the dosage form itself or to its packaging. 7.The pharmaceutical dosage form of claim 6 wherein the dosage form is atablet and the graphical illustration is applied to the tablet surface.8. The pharmaceutical dosage form of claim 6 wherein the at least oneactive ingredient comprises at least one vitamin.
 9. The pharmaceuticaldosage form of claim 6 wherein the at least one active ingredientcomprises the active ingredients pyridoxine HCl and doxylaminesuccinate.
 10. A method of diminishing the perception of teratogenicrisk among pregnant women taking a pharmaceutical dosage form containingat least one active ingredient, said method comprising providingpregnant women with the pharmaceutical dosage form bearingpregnancy-friendly indicia so as to graphically confirm thenon-teratogenic aspect of the pharmaceutical dosage form.
 11. The methodof claim 10 wherein said pregnancy-friendly indicia is in the shape of agraphical illustration of a pregnant woman applied to the dosage formitself or to its packaging.
 12. The method of claim 10 wherein the atleast one active ingredient comprises at least one vitamin.
 13. Themethod of claim 10 wherein the at least one active ingredient comprisesthe active ingredients pyridoxine HCl and doxylamine succinate.
 14. Themethod of claim 10 wherein the pharmaceutical dosage form is an oraldosage form.
 15. A method of improving patient compliance of pregnantwomen with medically recommended dosage regimen of at least one activeingredient, said method comprising providing pregnant women with apharmaceutical dosage form bearing pregnancy-friendly indicia so as tographically confirm the non-teratogenic aspect of the pharmaceuticaldosage form and thereby achieve greater patient compliance with themedically recommended dosage regimen.
 16. The method of claim 15 whereinsaid pregnancy-friendly indicia is in the shape of a graphicalillustration of a pregnant woman applied to the dosage form itself or toits packaging.
 17. The method of claim 15 wherein the at least oneactive ingredient comprises at least one vitamin.
 18. The method ofclaim 15 wherein the at least one active ingredient comprises the activeingredients pyridoxine HCl and doxylamine succinate.
 19. The method ofclaim 15 wherein the pharmaceutical dosage form is an oral dosage form.20. A method of improving patient compliance of pregnant women withmedically recommended dosage regimen of at least one active ingredientand consequently and simultaneously improving the therapeuticeffectiveness of said active ingredient(s), said method comprisingproviding pregnant women with a pharmaceutical dosage form bearingpregnancy-friendly indicia to graphically confirm the non-teratogenicaspect of said dosage form so as to elicit better patient compliancewith the medically recommended dosage regimen.
 21. The method of claim20 wherein said pregnancy-friendly indicia is in the shape of agraphical illustration of a pregnant woman applied to the dosage formitself or to its packaging.
 22. The method of claim 20 wherein the atleast one active ingredient comprises at least one vitamin.
 23. Themethod of claim 20 wherein the at least one active ingredient comprisesthe active ingredients pyridoxine HCl and doxylamine succinate.
 24. Themethod of claim 20 wherein the pharmaceutical dosage form is an oraldosage form.
 25. A method of diminishing the incidence of erroneousingestion by pregnant women of therapeutic agents not prescribed to saidpregnant women, said method comprising providing pregnant women with apharmaceutical dosage form comprising at least one active ingredientprescribed to said pregnant women, said dosage form bearingpregnancy-friendly indicia apt to graphically distinguish dosage formsintended to be used during pregnancy from others.
 26. The method ofclaim 25 wherein said pregnancy-friendly indicia is in the shape of agraphical illustration of a pregnant woman applied to the dosage formitself or to its packaging.
 27. The method of claim 25 wherein the atleast one active ingredient comprises at least one vitamin.
 28. Themethod of claim 25 wherein the at least one active ingredient comprisesthe active ingredients pyridoxine HCl and doxylamine succinate.
 29. Themethod of claim 25 wherein the dosage form is an oral dosage form.
 30. Amethod of diminishing the incidence of erroneous dispensing ofpharmaceutical dosage forms not intended for pregnant women, said methodcomprising providing a pharmaceutical dosage form, intended for use bypregnant women, comprising at least one active ingredient and bearingpregnancy-friendly indicia apt to graphically distinguish dosage formsintended to be used during pregnancy from others.
 31. The method ofclaim 30 wherein said pregnancy-friendly indicia is in the shape of agraphical illustration of a pregnant woman applied to the dosage formitself or to its packaging.
 32. The method of claim 30 wherein the atleast one active ingredient comprises at least one vitamin.
 33. Themethod of claim 30 wherein the at least one active ingredient comprisesthe active ingredients pyridoxine HCl and doxylamine succinate.
 34. Themethod of claim 30 wherein the dosage form is an oral dosage form.